With age, a host of complex biological changes occur in tissues which often result in an impaired capacity to mount a regenerative response to injury and disease. This leads to decreases in basic cognitive, sensory and motor functions and, in turn, a decreased quality of life. Numerous human conditions could be significantly improved if therapies that encourage tissue regeneration were available. In addition to stem cell-based strategies, alternative approaches exploit the inherent regenerative capacity of non-mammalian models to define the molecular events that permit tissue regeneration. We have developed and validated a powerful zebrafish regeneration model to unravel the complex process of vertebrate tissue regeneration. Our studies indicate that a number of genes are induced and repressed over the course of the regenerative process and that specific small regulatory RNAs are also coordinately differentially expressed. It is now widely accepted that the majority of genes are regulated by small non-coding RNAs. Preliminary data obtained in adult fin tissue revealed that over 100 small RNAs are differentially expressed during regeneration and many of these microRNAs (miRNAs) are predicted to regulate the expression of genes known to drive the regenerative process. Aging negatively impacts tissues' regenerative capacity and miRNA expression is reportedly increased in multiple models of aging. Since our preliminary data suggests that repression of key miRNAs is necessary to elicit a regenerative response, we hypothesize that specific miRNA expression will increase with age and directly leads to decreased regenerative capacity. By defining and comparing global small RNA and mRNA expression in aged, adult, and larval tissue coupled with mechanistic evaluation of miRNA-mRNA relationships in vivo, we will shed light on the molecular and genetic pathways that coordinately function to accomplish regeneration. These studies will put us in a position to begin to understand the role of miRNA in aging and regeneration and more broadly, help to explain why mammals fail to respond to tissue injury with a regenerative response. The full characterization of miRNAs in multiple complementary regeneration paradigms will make possible the identification of the key regulatory events that promote or limit wounding healing and regeneration. PUBLIC HEALTH RELEVANCE: Tissue loss from age-related disease and injury is a major cause of decreased quality of life. Understanding the complex signaling pathways that underly tissue regeneration will provide new avenues for developing novel therapeutics to help slow and/or prevent age-related tissue loss.